The first 18 issues featured the "Archie gang" in stories that were a bit more "off the wall" than the normal Archie series. The idea was to produce stories that made no sense. The title Mad House was written as two words instead of one to suggest a false connection to MAD Magazine and recapture its success. Beginning with issue 19, the Archie gang was dropped (though it was still called Archie's Mad House), and the title began featuring monsters, space stories and other wacky short stories. The gags in the comics often parodied the latest fads and popular culture. For a time, it would focus on stories with what were intended to be one-off characters. There were, however, exceptions to this rule. If a character became popular enough, he or she would appear again.

Perhaps the most noteworthy installment was issue 22 when Sabrina the Teenage Witch was introduced, with art by Archie mainstay Dan Decarlo. This issue has become one of the most sought after Archie issues of the Silver Age. Sabrina began making intermittent appearances through issue 74, and then transitioned over to other titles, such as Archie's TV Laugh-Out and her own Sabrina title. Other recurring characters included a bungling but victorious superhero named Captain Sprocket and a hippie named Clyde Didit (occasionally spelled Diddit) who served as a mascot for a while.

Shortly before Sabrina's departure, the title began a seies of name changes, morphing into Madhouse Ma-ad Jokes, Madhouse Ma-ad Freakout, and Madhouse Glads. Issues #95-97 were published under the Red Circle Comics Group logo and published horror. It was renamed Madhouse Comics for issue 98-130 and returned to humor. The Madhouse Glads run introduced yet another "gang" into the Archie universe, but much like the "gang" introduced in That Wilkin Boy, several years earlier, the "Madhouse Glads" gang never caught on with fans like the Josie gang did. Madhouse then returned to the series' irregular, nonsensical style before finally being discontinued.